Prolactin (PRL) and Its Receptor: Actions, Signal Transduction Pathways and Phenotypes Observed in PRL Receptor Knockout Mice

Abstract

PRL is an anterior pituitary hormone that, along with GH and PLs, forms a family of hormones that probably resulted from the duplication of an ancestral gene. The PRLR is also a member of a larger family, known as the cytokine class-1 receptor superfamily, which currently has more than 20 different members. PRLRs or binding sites are widely distributed throughout the body. In fact, it is difficult to find a tissue that does not express any PRLR mRNA or protein. In agreement with this wide distribution of receptors is the fact that now more than 300 separate actions of PRL have been reported in various vertebrates, including effects on water and salt balance, growth and development, endocrinology and metabolism, brain and behavior, reproduction, and immune regulation and protection. Clearly, a large proportion of these actions are directly or indirectly associated with the process of reproduction, including many behavioral effects. PRL is also becoming well known as an important regulator of immune function. A number of disease states, including the growth of different forms of cancer as well as various autoimmune diseases, appear to be related to an overproduction of PRL, which may act in an endocrine, autocrine, or paracrine manner, or via an increased sensitivity to the hormone. The first step in the mechanism of action of PRL is the binding to a cell surface receptor. The ligand binds in a two-step process in which site 1 on PRL binds to one receptor molecule, after which a second receptor molecule binds to site 2 on the hormone, forming a homodimer consisting of one molecule of PRL and two molecules of receptor. The PRLR contains no intrinsic tyrosine kinase cytoplasmic domain but associates with a cytoplasmic tyrosine kinase, JAK2. Dimerization of the receptor induces tyrosine phosphorylation and activation of the JAK kinase followed by phosphorylation of the receptor. Other receptor-associated kinases of the Src family have also been shown to be activated by PRL. One major pathway of signaling involves phosphorylation of cytoplasmic State proteins, which themselves dimerize and translocate to nucleus and bind to specific promoter elements on PRL-responsive genes. In addition, the Ras/Raf/MAP kinase pathway is also activated by PRL and may be involved in the proliferative effects of the hormone. Finally, a number of other potential mediators have been identified, including IRS-1, PI-3 kinase, SHP-2, PLC gamma, PKC, and intracellular Ca2+. The technique of gene targeting in mice has been used to develop the first experimental model in which the effect of the complete absence of any lactogen or PRL-mediated effects can be studied. Heterozygous (+/-) females show almost complete failure to lactate after the first, but not subsequent, pregnancies. Homozygous (-/-) females are infertile due to multiple reproductive abnormalities, including ovulation of premeiotic oocytes, reduced fertilization of oocytes, reduced preimplantation oocyte development, lack of embryo implantation, and the absence of pseudopregnancy. ...

Prolactin gene-disruption arrests mammary gland development and retards T-antigen-induced tumor growth

“…Sections were stained with hematoxylin/eosin, photographed and reproduced at a magni®cation of 5006. Examples of metaplastic transformation (white arrow, left panel) and invasion into surrounding stroma (black arrow, right panel) are identi®ed Jak2 protein-tyrosine kinase, and phosphorylation of various substrates including Stat proteins (Bole-Feysot et al, 1998). According to the current understanding of the Stat activation, tyrosine phosphorylation of Stat proteins leads to dimerization through SH2-domain interactions.…”

Prolactin modulates phosphorylation, signaling and trafficking of epidermal growth factor receptor in human T47D breast cancer cells

“…Although controversial, the contribution of PRL to the pathogenesis and progression of human breast cancer is increasingly appreciated (Hankinson et al, 1999;Vonderhaar, 1999;Llovera et al, 2000b;Ben-Jonathan et al, 2002;Clevenger et al, 2003). PRL signals via the PRL receptor (PRLR), a cytokine receptor family member, which possesses no intrinsic tyrosine kinase activity and couples to the nonreceptor tyrosine kinase, Janus kinase (JAK)2 (Bazan, 1990;Argetsinger et al, 1993;Campbell et al, 1994;Rui et al, 1994;Bole-Feysot et al, 1998). Among other pathways, PRL activates the extracellular signal-regulated kinase (ERK) and STAT signaling pathways, with STAT5a being the principal STAT isoform involved in its mammary effects (Campbell et al, 1994;Rui et al, 1994;Liu et al, 1997;Clevenger and Kline, 2001).…”

Human prolactin (hPRL) antagonists inhibit hPRL-activated signaling pathways involved in breast cancer cell proliferation

“…Prolactin (PRL) is a polypeptidic hormone secreted mainly by the anterior pituitary, that exerts multiple biological activities (reviewed by Bole-Feysot et al, 1998). In the mammary gland, it participates in lobulo-alveolar development, alveolar cell growth and milk protein synthesis, acting as a proliferation and di erentiation factor (depending on the development stage).…”